We have studied structural remodeling and biochemical changes that occur in the rat aortic wall during aging. Luminal diameter and wall thickness increased with aging between 6 and 30 month by 25.6% (p lesser than0.001) and 38.4% (p lesser than 0.001) respectively. The density of medial cells decreased by 18.4% (p lesser than 0.001) over this age range. The development of a subendothelial space resulted in a 5-fold increase in intimal thickness in old rats, in which most of the cells were identifie as SMC. Regional disruption of the internal elastic lamina was observed in aortae of old rats, suggesting possible involvement of a proteolytic activity in the formation of the thickened intima. Enhanced expression of ICAM-1, TGF-beta and MMP-2 was observed in the thickened intima of old rats. In aortic extracts from old vs. young rats, fibronectin increased 5-fold (p lesser than 0.001). These results indicate that remodeling of the arterial wall with aging includes increases of aortic diameter and wall thickness as well as a decrease in cellularity, and may involve a TGF-beta-regulated accumulation of fibronectin. An enhanced amount and activity of MMP-2 in the thickened intima suggests a role for this enzyme in the age-related remodeling, involving both cells and extracellular matrix. In vitro, SMC from old rats stimulated by cytokines, including IL-1, TNF-alpha and TGF-beta, secreted a greater amount of MMP-2 than those of young rats (54.17%, 42.52%, and 11.27% above that at the young age respectively). This suggests that, in vivo, levels of cytokines may increase with aging. In addition, SMC in vitro cultured from old rats exhibit a greater proliferation rate and enhanced chemotaxis than SMC from young rats. Decreases in myosin, actin and vimentin (59.6%, 41.2% and 54.8% respectively) and increases in desmin and tubulin (41.6% and 65.1% respectively) occurred in SMC from old rats and may relate to their altered phenotype with respect to enhanced proliferation and migration. The aggregate findings of this project to date may explain, in part, the decreased vascular compliance that occurs with aging and age-associated increase in vascular diseases.